benzoyl peroxide/tretinoin topical (Rx)

>10%

Erythema, mild (33%)

Pigmentation, mild (27.3%)

Dryness, mild (22.3%)

Scaling, mild (16.4%)

Itching, mild (11.1%)

Application site pain (10.6%)

1-10%

Erythema, moderate (6.9%)

Pigmentation, moderate (6.3%)

Burning, mild (5.9%)

Stinging, mild (5.3%)

Dryness, moderate (5.3%)

Application site dryness (4.9%)

Application site exfoliation (4.1%)

Application site erythema (4%)

Scaling, moderate (2.6%)

Burning, moderate (2.2%)

Itching, moderate (1.8%)

Application site dermatitis (1.3%)

Application site pruritus (1.3%)

Application site irritation (1.1%)

<1%

Pigmentation, severe (0.4%)

Dryness, severe (0.4%)

Stinging, moderate (0.2%)

Erythema, severe (0.2%)

Postmarketing Reports

Immune system disorders: Anaphylaxis, angioedema, and urticaria

Contraindications

Hypersensitivity to benzoyl peroxide or any components of the product

Cautions

Severe hypersensitivity reactions (eg, anaphylaxis, angioedema) reported with use of benzoyl peroxide products; if a serious hypersensitivity reaction occurs, discontinue therapy immediately and initiate appropriate therapy

Pain, dryness, exfoliation, erythema, and irritation may occur

Avoid application to cuts, abrasions, eczematous, or sunburned skin

Minimize unprotected exposure to sunlight and sunlamps; use sunscreen and protective clothing when sun exposure cannot be avoided; discontinue therapy at first evidence of sunburn

Pregnancy

No data are available on use in pregnant females

Topical tretinoin: Available data from published observational studies in pregnant females have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes

Topical benzyl peroxide: Studies conducted with topical benzoyl peroxide have not demonstrated systemic absorption and maternal use is not expected to result in fetal exposure to benzoyl peroxide

Animal data

• No animal reproductive studies have been conducted with benzoyl peroxide/tretinoin topical or benzoyl peroxide

• Tretinoin

  • Topical administration to pregnant rats during organogenesis was associated with malformations (craniofacial abnormalities [hydrocephaly], asymmetrical thyroids, variations in ossification, and increased supernumerary ribs) at doses >1 mg tretinoin/kg/day, ~5x the maximum recommended human dose (MRHD) based on body surface area (BSA) comparison and assuming 100% absorption
  • Oral administration to pregnant cynomolgus monkeys during organogenesis was associated with malformations at 10 mg/kg/day (~100 times the MRHD based on BSA comparison and assuming 100% absorption)

Lactation

No data available on presence of benzoyl peroxide and tretinoin or its metabolites in human milk, effects on breastfed infants, or effects on milk production

Unknown whether topical administration of tretinoin could result in sufficient systemic absorption to produce detectable concentrations in human milk

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Benzoyl peroxide: Oxidizing agent with bactericidal and keratolytic effects; precise mechanism of action is unknown

Tretinoin

• Metabolite of vitamin A that binds with high affinity to specific retinoic acid receptors located in both the cytosol and nucleus
• Activates three members of the retinoic acid (RAR) nuclear receptors (RARα, RARβ, and RARγ) which act to modify gene expression, subsequent protein synthesis, and epithelial cell growth and differentiation
• It has not been established whether clinical effects of tretinoin are mediated through activation of retinoic acid receptors and/or other mechanisms
• In the treatment of acne, current evidence suggests that tretinoin decreases cohesiveness of follicular epithelial cells with decreased microcomedo formation; additionally, tretinoin stimulates mitotic activity and increased turnover of follicular epithelial cells causing extrusion of the comedones

Absorption

Steady-state PK characteristics were determined from samples drawn on Day 14

Peak plasma concentration

• Tretinoin

  • 9-11 years: 0.18 ± 0.22 ng/mL
  • 12-17 years: 0.19 ± 0.18 ng/mL
  • ≥18 years: 0.15 ± 0.17 ng/mL

• 4-keto 12-cis RA

  • 9-11 years: 0.34 ± 0.36 ng/mL
  • 12-17 years: 0.32 ± 0.28 ng/mL
  • ≥18 years: 0.27 ± 0.29 ng/mL

• 13-cis RA

  • 9-11 years: 0.13 ± 0.09 ng/mL
  • 12-17 years: 0.28 ± 0.35 ng/mL
  • ≥18 years: 0.21 ± 0.19 ng/mL

AUC

• Tretinoin

  • 9-11 years: 2.06 ± 3.96 ng⋅h/mL
  • 12-17 years: 1.56 ± 1.97 ng⋅h/mL
  • ≥18 years: 0.63 ± 0.95 ng⋅h/mL

• 4-keto 12-cis RA

  • 9-11 years: 2.89 ± 3.17 ng·h/mL
  • 12-17 years: 2.39 ± 3.05 ng·h/mL
  • ≥18 years: 2.88 ± 3.61 ng·h/mL

• 13-cis RA

  • 9-11 years: 0.96 ± 1.36 ng·h/mL
  • 12-17 years: 1.79 ± 2.79 ng·h/mL
  • ≥18 years: 1.99 ± 2.90 ng·h/mL

Topical Administration

Topical use only

Not for oral, ophthalmic, or intravaginal use

Avoid contact with eyes, lips, paranasal creases, and mucous membranes

Inform patients that application may bleach hair or colored fabric

Wash hands after application

Storage

Unopened bottle: Refrigerate at 2-8ºC (36-46ºF) until dispensed

After dispensing: Store at room temperature 20-25ºC (68-77ºF); discard 12 weeks after date of dispensing or 30 days after first opening, whichever is sooner

Do NOT freeze